Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. Our proposal builds a collaborative network of researchers and healthcare providers, all with a stake in improving healthcare and outcomes for persons affected by various rare genetic disorders. Our approach will synergize basic and clinical research with the use of cutting-edge phenotyping technologies, an array of world class experts, and the translation of whole exome sequencing to the bedside. This will result in the development of a diagnostic process, rapidly translating clinical evidence into improved healthcare delivery. The Undiagnosed Disease Network (UDN) will provide the foundation to stimulate additional multi-and interdisciplinary basic, translational, and clinical research. Investigating rare diseases involving multiple systems and incorporating comprehensive genomic data into clinical care creates considerable challenges, from the interpretation of vast amounts of genetic variants to their relevance to the symptoms, to the communication issues linked to their disclosure, and to their impact on clinical management. Our proposal delivers a platform for a UDN Clinical Site that functions locally and as part of a network to tackle the incorporation of genomic information into the clinical workflow, analyze patients' symptoms in a standardized and reproducible fashion, and perform research investigations to elucidate further the mechanisms of undiagnosed diseases. We will reach these overarching goals by implementing the following specific aims: Aim 1: Create a UDN clinic model that functions locally and network-wide Aim 2: Investigate the clinical phenotypes of new and rare disorders Aim 3: Investigate the underlying mechanisms of new and rare disorders Aim 4: Build a network-wide sustainable infrastructure for translational research on new and rare disorders Our project integrates the resources of (1) the infrastructure of a Clinical and Translational Science Institute, allowing for a state-of-the-art clinical investigation of complex, multisystemic disorders, within a maximum of a week stay; (2) an experienced, team of clinicians from all specialty fields, that delivers clinical use of whole- exome sequencing, and it integration in the diagnostic process of rare, undiagnosed disorders; (3) the UCLA Clinical Genomic Center that offers bioinformatics data handling, and clinical laboratory exome sequencing, that will interpret and report clinically relevant DNA variants; (4) expertise in the investigation of environmental effects on clinical symptoms; (5) a registry infrastructure with longstanding experience in standardization of phenotypic and genotypic information; (6) access to a large, ethnically varied population and (7) a sustainable approach, with provisions to care for un/underinsured patients. Overall, our approach is designed to work cooperatively with the other Clinical Sites, the Coordinating Center, and the IRP-UDP, by capitalizing on our experiences in medical genetics, genetic counseling, clinical exome sequencing, and statistical genomics.